Benzodioxole compounds

ABSTRACT

WHEREIN R1 is hydrogen, lower alkyl, aryl, haloaryl, lower-alkylaryl, lower-alkoxyaryl, methylenedioxyaryl, ethylenedioxyaryl, trifluoromethylaryl, nitroaryl or aminoaryl, R2 is lower-alkyl, aryl, haloaryl, lower-alkylaryl, loweralkoxyaryl, methylenedioxyaryl, ethylenedioxyaryl, trifluoromethylaryl, nitroaryl or aminoaryl, or R1 R2 are -(CH2)4-, -(CH2)5- or -(CH2)6- and Het is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinazolinyl,1,3,5-triazinyl or 1,3-thiazoyl, each being optionally substituted by lower-alkyl, lower-alkoxy, hydroxyl or phenyl. These compounds are used as medicines especially as peripheral vasodilator agent and central nervous system stimulant. Benzodioxole compounds of the formula :

United States Patent [191 Regnier et al.

[ Nov. 4, 1975 BENZODIOXOLE COMPOUNDS [73] Assignee: Science-Union Et Cie, France [22] Filed: Mar. 16, 1973 [21] Appl. No.: 342,284

[30] Foreign Application Priority Data Apr. 7, 1972 United Kingdom 16098/72 [52] US. Cl. 260/256.4 N; 260/248 CS; 260/250 A; 260/250 R; 260/256-4 Q; 260/268 N;

[51] Int. Cl. C07D 405/14 [58] Field of Search 260/256.4 Q, 256.4 N

[56] References Cited UNITED STATES PATENTS 3,299,067 l/1967 Regnier et al. 260/256.4

Primary Examiner-James A. Patten Attorney, Agent, or Firm-Gordon W. l-lueschen [57] ABSTRACT Benzodioxole compounds of the formula CH N Het R2 0 2 I wherein R is hydrogen, lower alkyl, aryl, haloaryl, lower-alkylaryl, lower-alkoxyaryl, methylenedioxyaryl, ethylenedioxyaryl,

trifluoromethylaryl, nitroaryl or aminoaryl,

R is lower-alkyl, aryl, haloaryl, lower-alkylaryl, lower-alkoxyaryl, methylenedioxyaryl, ethylenedioxyaryl, trifluoromethylaryl, nitroaryl or aminoaryl, or

Het is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinazolinyLl,3,5-triazinyl or 1,3-thiazoyl, each being optionally substituted by lower-alkyl, lower-alkoxy, hydroxyl or phenyl.

These compounds are used as medicines especially as peripheral vasodilator agent and central nervous system stimulant.

3 'Claims, No Drawings wherein R and R have the meaning given above, and 'BENZODIOXOLE COMPOUNDS also, by condensing a compound of the general formula The present invention provides benzodioxole com- IV:- pounds of the general formula I: v a l i I jg Z 'Iv R h V 7 I i u C .1 CH -Het I. 2 R ,2 l, O I g I 2 2 V wherein R is selected from the group consisting ofa hydrogen atom, an alkyl radical having from 1 to 5 carbon atoms inclusi e,"an unsubstituted aryl radical and an arylradical substitutedby one or more substituents selected from the group consisting of halogen atoms, for example fluorine and chlorine atoms, alkyl and alkoxy radicals each having from 1 to 5 carbon atoms inclusive, methylenedioxy, ethylenedioxy, trifluorornethyl, nitro and amino radicals; v R is selected from the group consisting of an alkyl radical having from I ,to 5 carbon atoms inclusive, an unsubstituted aryl radical and an aryl radical substitutedby one or more substituents sel'cted from the group consisting of halogen atoms, for example fluorine and chlorine atoms, alkyl and alkoxy radicals each having from 1 to 5 .carbon atoms inclusive, methylenedioxy, ethylenedioxy, tnifluo romethyl, nitro and amino radicals; and R and R together represent a polymethylenic chain I of the formula (CH wherein ,n is se ected from 4, 5 and 6; and

nitrogen atoms and optionally one sulfur atom, se-

. lected from the group consisting of pryidyl, ;iyrimidinyl, pyridazinyl, pyrazinyl, quinazolinyl, l,3,5-

triazinyl and, 1,3-thiazolyl radicals and e ch of ,these radicals substitutedby one or more, substituents selected from the group consisting of alkyl and alkoxy radicals each having from 1 to 5 carbon atoms inclusive, hydroxyl and phenyl radicals; and acid addition salts, especially physiologically tolerable acid addition salts, thereof. .The compoundsof. the general formula I are new. They were prepared by condensing a compound of the general fon'nula II: t

Het Z 7 ll wherein Het has the meanings given above and Z reprewith a compound of the general formula V:

Het-N NH v wherein Z, R R and Het have the meanings given above.

The condensation processes of the inventionare advantageously carried out in a polar solvent, for example in an alcohol having a high boiling point, for example butanol or pentanol or, preferably, in an aliphatic amide for example dimethylformamide or dimethylacetamide; or in an non-polar solvent such as an aromatic hydrocarbon, for example toluene or xylene. The processes are advantageous carried out at a temperature within the range of from to C in the presence of an acceptor of the hydrogen halide formed during the'reaction. As an acceptor there may be used, for example, an alkali or alkaline earth metal salt of carbonic acid, for example sodium or potassium bicarbonate or carbonate or calcium carbonate, a tertiary organic base, for example dimethylaniline, pyridine or triethylamine oran excess of the compound of the formula Ill or VS r The "compounds of the present invention are weak bases which may be converted with acids into acid ad dition salts. As acids used to form these salts, there may be especially mentioned, for example, in the mineral seriesz'hydrochloric, hydrobromic, sulfuric and phosphoric acids and in the organic series: acetic, propionic, maleic, fumaric, tartaric, citric, oxalic, benzoic, methanesulfonic a'nd isethionic acids.

The compounds of the general formula I and acid addition salts thereof may be purified by, for example, crystallisation or chromatographic absorption.

Thefollowing examples illustrate the invention. The meltingpoints were determined in a capillary tube sentsa chlorine or bromine atom, with a compound of 5-5 ap) of on block U)- the general formula Ills.

N H n i ExAMPLEI .-5-[4-(-;Z-pyrimidinyl)-l piperazinyl] methyl- 2-phenyl a: .benzo [d]-l,3- dioxole A solution of 8 .5 g (0.0344 mole) of 5-chloromethyl- 2 -phenyl benzo [d]-1,3-dioxole (BP/0.05mm

l35-l37 C) and 11.3 g (0.0689 mole) of l-(2- EXAMPLE 25 4-( 2-pyrimidinyl 1 -piperazinyl] methyl-2-phenyl benzo [d]-l,3-dioxole A solution of 5.7 g (0.05 mole) of 2-chloropyrimidine and 14.7 g (0.05 mole) of 5-(l-piperazinyl methyl)-2-phenyl benzo [d]-l,3-dioxole in 200 ml of dimethylformamide was refluxed for 9 hours in the presence of 13.8 g of dry potassium carbonate. The soobtained salt was suction-filtered off and the solvent was evaporated off under reduced pressure. The crystallised residue was washed with water, and was then recrystallised from 1 10 ml of cyclohexan e. There were obtained 15.2 g of 5-[4-(2-pyrimidinyl)-l piperazi yl] methyl-2-phenyl benzo [d]-1,3-dioxole, cr amcoloured crystals melting at (K) 106 C. 7

The starting compound, 5-( l-piperazinyl methy )-2- phenyl benzo [d]-1 ,3-dioxole, was prepared by hea ing, at 140 C, 5-chloromethyl-2-phenyl benzo [d] 1,3- dioxole with an excess of anhydrous piperazine.

The compounds of Examples 2 to 24 were also prepared according to the process described in Example 25.

The compounds of the present invention and pl lysiologically tolerable salts thereof possess valuable harmacological and therapeutic properties, especially peripheral vasodilator and central nervous system stimulant properties.

Their toxicity expressed in LD in mice varies from 125 to 1000 mg/kg by intraperitoneal route.

When administered to the dog intravenously atldoses of 0.5 to 5.0 mg/kg, an increase of the femoral output of to 100 is observed durably.

The scores of CNS stimulation or stereotypy were determined by the method of Quinton and Haliwel l, Nature 200, 178 (1963). Scores of up to 208 were ob served with doses of 20 to 80 mg/kg I.P.

These results permit the use of the present compounds in therapy, especially in the treatment of vasoconstriction or obliteration, as well as in CNS depression, particularly in parkinsonism.

The present invention also provides pharmaceutical compositions containing a compound of general formula l or a physiologically tolerable salt thereof in admixture or conjunction with a pharmaceutically suitable carrier, such, for example, as distilled water, glucose, lactose, starch, talc, magnesium stearate, ethyl cellulose or cocoa butter.

The so-obtained pharmaceutical compositions may be in form of tablets, dragees, capsules, suppositories or injectable or drinkable solutions and may be administered by oral, rectal or parenteral route at doses of 20 5 to 200 mg, 1 to 5 times a day.

pyrimidinyl 1 -piperazi nyl] [d 1 ,3-dioxole.

We claim:

-N N-Het wherein:

R is selected from the group consisting of hydrogen and alkyl having 1 to 5 carbon atoms inclusive; R is selected from the group consisting of alkyl having 1 to 5 carbon atoms inclusive, phenyl, halophenyl, lower-alkylphenyll, lower-alkoxyphenyl, and trifluoromethylphenyl, R, being alkyl when R is alkyl; R and R together represent a polymethylenic chain (CH wherein n is selected from 4, 5 and. 6; and Het is pyrimidinyl, and B. physiologically tolerable acid addition salts thereof. 2. A compound selected from the group consisting of A. 5-[4-(2-pyrimidinyl)-l-piperazinyl]methyl-2- phenylbenzo[d]-1,3 -dioxole, 5-[4-( Z-pyrimidinyl 1-piperazinyl]methyl-Z-methyL 2-ethyl-benzo[d]-1 ,3-dioxole, 5-[4-( Z-pyrimidinyl 1-piperazinyl methyl-2,2-

cyclopentamethylen ebenzo[ d l 3-dioxole, 5- [4-( 2-pyrimidinyl 1 -piperazinyl methyl-2,2- cyclotetramethylen ebenzo[ d]- 1 ,3-dioxole,

. 5-[4-(2-pyrimidinyl)- 1-piperazinyl]methyl-2,2-

cyclohexamethylen ebenzo[d] -l ,3 -dioxole,

5-[ 4-( Z-pyrimidinyl 1 -piperazinyl -methyl-2-(pfluorophenyl)benzo [d]- l ,3-dioxole,

5- [4-( 2-pyrimidinyl l-piperazinyl -methyl-2-(mfluoropheny1)benzo [d]- l ,3-dioxole,

5-[ 4-( Z-pyrimidinyl 1-piperazinyl]-methyl-2-(mtolylbenzo[d]- l ,3-dioxole,

5- [4-( 2-pyrimidinyl 1 -piperazinyl methyl-2-( mmethoxyphenyl)benzo[d]-l ,3-dioxole,

5- [4-( Z-pyrimidinyl l -piperazinyl methyl-2-(m-trifluoromethylphenyl)benzo[d]- 1 ,3-dioxole, and

(B) a physiologically tolerable acid addition salt thereof.

3. A compound of claim 2 which is 5-[4-(2- methyl-Z-phenyl benzo l. A compound selected from the group consisting of:

A. benzodioxole compounds of the general fonnula:

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,917, 9 Dated Novelfber 7 Inventor(s) Gilbert Reqpier et al.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

[75] Imzentdrs: Gilbert Regnier, Chatehay-Malabry;

Col. 4, line 29; "methyl benzo [d]-l,3dioxole" should read methyL-Z-methyl benzo [d] l, 3-dioxole-- Signed and Scalccl this eighth Day of June1976 {sum RUTH C. MASON 4 C. MARSHALL DANN Arm-ting Officer I (ommiuilmer ailments and Trademark: 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: A. BENZODIOXOLE COMPOUNDS OF THE GENERAL FORMULA:
 2. A compound selected from the group consisting of A. 5-(4-(2-pyrimidinyl)-1-piperazinyl)methyl-2-phenylbenzo(d)-1,3-dioxole, 5-(4-(2-pyrimidinyl)-1-piperazinyl)methyl-2-methyl-2-ethyl-benzo(d)-1,3 -dioxole, 5-(4-(2-pyrimidinyl)-1-piperazinyl)methyl-2,2-cyclopentamethylenebenzo(d) -1,3-dioxole, 5-(4-(2-pyrimidinyl)-1-piperazinyl)methyl-2,2-cyclotetramethylenebenzo(d) -1,3-dioxole, 5-(4-(2-pyrimidinyl)-1-piperazinyl)methyl-2,2-cyclohexamethylenebenzo(d)-1,3-dioxole, 5-(4-(2-pyrimidinyl)-1-piperazinyl)-methyl-2-(p-fluorophenyl)benzo(d)-1,3 -dioxole, 5-(4-(2-pyrimidinyl)-1-piperazinyl)-methyl-2-(m-fluorophenyl)benzo(d)-1,3 -dioxole, 5-(4-(2-pyrimidinyl)-1-piperazinyl)-methyl-2-(m-tolylbenzo(d)-1,3-dioxole, 5-(4-(2-pyrimidinyl)-1-piperazinyl)methyl-2-(m-methoxyphenyl)benzo(d)-1,3 -dioxole, 5-(4-(2-pyrimidinyl)-1-piperazinyl)methyl-2-(m -trifluoromethylphenyl)benzo(d)-1,3-dioxole, and (B) a physiologically tolerable acid addition salt thereof.
 3. A compound of claim 2 which is 5-(4-(2-pyrimidinyl)-1-piperazinyl) methyl-2-phenyl benzo (d)-1,3-dioxole. 